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TitleProbing the mechanism by which the retinal G protein transducin activates its biological effector PDE6.
Journal, issue, pagesJ Biol Chem, Vol. 300, Issue 2, Page 105608, Year 2024
Publish dateDec 28, 2023
AuthorsCody Aplin / Richard A Cerione /
PubMed AbstractPhototransduction in retinal rods occurs when the G protein-coupled photoreceptor rhodopsin triggers the activation of phosphodiesterase 6 (PDE6) by GTP-bound alpha subunits of the G protein ...Phototransduction in retinal rods occurs when the G protein-coupled photoreceptor rhodopsin triggers the activation of phosphodiesterase 6 (PDE6) by GTP-bound alpha subunits of the G protein transducin (Gα). Recently, we presented a cryo-EM structure for a complex between two GTP-bound recombinant Gα subunits and native PDE6, that included a bivalent antibody bound to the C-terminal ends of Gα and the inhibitor vardenafil occupying the active sites on the PDEα and PDEβ subunits. We proposed Gα-activated PDE6 by inducing a striking reorientation of the PDEγ subunits away from the catalytic sites. However, questions remained including whether in the absence of the antibody Gα binds to PDE6 in a similar manner as observed when the antibody is present, does Gα activate PDE6 by enabling the substrate cGMP to access the catalytic sites, and how does the lipid membrane enhance PDE6 activation? Here, we demonstrate that 2:1 Gα-PDE6 complexes form with either recombinant or retinal Gα in the absence of the Gα antibody. We show that Gα binding is not necessary for cGMP nor competitive inhibitors to access the active sites; instead, occupancy of the substrate binding sites enables Gα to bind and reposition the PDE6γ subunits to promote catalytic activity. Moreover, we demonstrate by reconstituting Gα-stimulated PDE6 activity in lipid bilayer nanodiscs that the membrane-induced enhancement results from an increase in the apparent binding affinity of Gα for PDE6. These findings provide new insights into how the retinal G protein stimulates rapid catalytic turnover by PDE6 required for dim light vision.
External linksJ Biol Chem / PubMed:38159849 / PubMed Central
MethodsEM (single particle)
Resolution3.0 - 4.44 Å
Structure data

EMDB-42208, PDB-8ufi:
Cryo-EM structure of bovine phosphodiesterase 6
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-42220, PDB-8ugb:
Cryo-EM structure of bovine phosphodiesterase 6 bound to udenafil
Method: EM (single particle) / Resolution: 3.0 Å

EMDB-42234, PDB-8ugs:
Cryo-EM structure of bovine phosphodiesterase 6 bound to cGMP
Method: EM (single particle) / Resolution: 3.2 Å

EMDB-42235: Bovine rod phosphodiesterase 6 bound to one retinal transducin alpha subunit
Method: EM (single particle) / Resolution: 4.15 Å

EMDB-42237: Bovine rod phosphodiesterase 6 bound to two retinal transducin alpha subunits
Method: EM (single particle) / Resolution: 4.24 Å

EMDB-42238: Bovine rod phosphodiesterase 6 bound to two chimera transducin alpha subunits without a stabilizing antibody
Method: EM (single particle) / Resolution: 4.44 Å

EMDB-42358, PDB-8ulg:
Cryo-EM structure of bovine phosphodiesterase 6 bound to IBMX
Method: EM (single particle) / Resolution: 3.2 Å

Chemicals

ChemComp-PCG:
CYCLIC GUANOSINE MONOPHOSPHATE

ChemComp-ZN:
Unknown entry

ChemComp-MG:
Unknown entry

ChemComp-ZUD:
Udenafil

ChemComp-IBM:
3-ISOBUTYL-1-METHYLXANTHINE / inhibitor, antagonist*YM

Source
  • bos taurus (cattle)
KeywordsSIGNALING PROTEIN / phosphodiesterase / GPCR effector enzyme / SIGNALING PROTEIN/INHIBITOR / inhibitor / SIGNALING PROTEIN-INHIBITOR complex

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